Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular basis of human leukemia is heterogeneous. Cytogenetic findings are increasingly associated with molecular abnormalities, some of which are being understood at the functional level. Specific therapies can be developed based on such knowledge. To search for new genes in the acute leukemias, we performed a representational difference analysis. We describe a human gene in chromosome 8q22.3, BAALC (brain and acute leukemia, cytoplasmic), that is highly conserved among mammals but evidently absent from lower organisms. We characterized BAALC on the genomic level and investigated its expression pattern in human and mouse, as well as its complex splicing behavior. In vitro studies of the protein showing its subcellular localization suggest a function in the cytoskeleton network. Two isoforms are specifically expressed in neuroectoderm-derived tissues, but not in tumors or cancer cell lines of nonneural tissue origin. We show that blasts from a subset of patients with acute leukemia greatly overexpress eight different BAALC transcripts, resulting in five protein isoforms. Among patients with acute myeloid leukemia, those overexpressing BAALC show distinctly poor prognosis, pointing to a key role of the BAALC products in leukemia. Our data suggest that BAALC is a gene implicated in both neuroectodermal and hematopoietic cell functions.
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PMID:BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. 1170 1

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). Of adults with de novo AML, 45% lack cytogenetic abnormalities, and identification of predictive molecular markers might improve therapy. We studied the prognostic impact of BAALC (Brain And Acute Leukemia, Cytoplasmic), a novel gene involved in leukemia, in 86 de novo AML patients with normal cytogenetics who were uniformly treated on Cancer and Leukemia Group B 9621. BAALC expression was determined by comparative real-time reverse transcriptase-polymerase chain reaction in pretreatment blood samples, and patients were dichotomized at BAALC's median expression into low and high expressers. Low expressers had higher white counts (P =.03) and more frequent French-American-British M5 morphology (P =.007). Compared to low expressers, high BAALC expressers showed significantly inferior overall survival (OS; median, 1.7 vs 5.8 years, P =.02), event-free survival (EFS; median, 0.8 vs 4.9 years, P =.03), and disease-free survival (DFS; median, 1.4 vs 7.3 years, P =.03). Multivariable analysis confirmed high BAALC expression as an independent risk factor. For high BAALC expressers the hazard ratio of an event for OS, EFS, and DFS was respectively 2.7, 2.6, and 2.2. We conclude that high BAALC expression predicts an adverse prognosis and may define an important risk factor in AML with normal cytogenetics.
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PMID:BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. 1275 Jan 67

PURPOSE To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene- and microRNA-expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.
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PMID:Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. 1945 32

Alkylating agents, topoisomerase II inhibitors, ionizing radiation, and other hematotoxins induce DNA damage in hematopoietic stem cells that results in lesions such as balanced and unbalanced chromosome rearrangements, -5/del(5q) and/or -7/del(7q), as well as other submicroscopic genetic lesions. Together with epigenetic alterations, these result in dysplasia, clonal expansion, and ultimately myeloid leukemia. Combinations of lesions are required to induce overt leukemia. Altering a small subset of signaling pathways leads to disruption of normal self-renewal, proliferation, differentiation, and apoptotic mechanisms that control the development of hematopoietic stem cells and their differentiation into mature effector cells. Recent studies have shown that cytogenetically normal (CN-) AML is quite heterogeneous at the molecular level. Patients with CN-AML harboring mutations in NPM1, FLT3, CEBPA, WT1 or expressing high levels of BAALC, ERG, or MN1 have distinctly different clinical outcomes. NPM1 mutations are independently associated with higher remission rates and longer disease-free and overall survival in AML. Copy number alterations (CNAs) are deletions or amplifications of single genes. CNAs have been found at the breakpoints of known chromosomal translocations. Fewer CNAs have been detected in AML than in pediatric ALL. Micro-RNAs (miRs) are non-coding small RNA molecules containing about 22 nucleotides that are typically encoded within introns. They hybridize to complementary mRNA targets and modulate protein expression by inhibiting translation and/or inducing degradation of target messenger RNAs. This new class of genes has recently been shown to play a pivotal role in malignant transformation. miRs are down-regulated in many tumors and thus appear to function as tumor suppressor genes. Distinctive genome-wide miR expression profiles have been associated with different subsets of AML. A miR signature that is associated with clinical outcome in patients with high-risk molecular features of AML (those who have FLT3-ITD or wild-type NPM1) has been reported. This subgroup constitutes approximately 65% of patients with CN-AML and one-third of all patients with AML <60 years old. Down-regulation of the miR-181 family contributes to an aggressive leukemia phenotype through mechanisms associated with the activation of pathways of innate immunity mediated by toll-like receptors and interleukin-1beta.
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PMID:Micro-RNAs and copy number changes: new levels of gene regulation in acute myeloid leukemia. 1982 34

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). However, about 50% of newly diagnosed acute myeloid leukemia (AML) cases have normal karyotype. These patients are very heterogenous with respect to acquired gene mutations and gene expression changes. The identification of these genetic alterations may lead to improved prognostification and generation of novel risk-adapted therapies. The aim of this work was to study the prognostic impact of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha) and expression of the BAALC gene (for brain and acute leukemia, cytoplasmic), a novel gene involved in leukemia, in 38 adults with AML and normal cytogenetics. Screening for mutations of CEBPA gene was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP), and BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in blood or bone marrow samples. CEBPA mutations were found in 7 (18.4%) of 38 patients, 36.8 % (14 of 38) had low BAALC expression and 63.2 % (24 of 38) had high BAALC expression. Patients with CEBPA mutations had favorable course of their disease. They had higher rate of complete remission (CR) (85.7 % vs 51.6 %; P = 0.108), lower incidence of relapse (0% vs. 41.9%; P = 0.038). Disease free survival (DFS) and overall survival (OS) were significantly longer for patients with CEBPA mutations compared with patients without mutations (mean 13.65 +/- 5.41 vs. 7.32 +/- 4.33 months, P = 0.047; mean 15.32 +/- 6.5 vs 8.5 +/- 3.21 months, P = 0.039; respectively). Compared to low BAALC expressers, high BAALC expressers had lower incidence of CR (50% vs 71.4%; P = 0.171), higher incidence of relapse (50% vs. 14.3%; P = 0.029), and showed significantly shorter DFS (mean 7.5 +/- 2.12 vs. 11.67 +/- 4.6 months, P = 0.038) and inferior overall survival (mean 9.1 +/- 3.52 vs. 13.22 +/- 4.21 months, P = 0.024). On multivariable analysis, wild-type CEBPA as well as high BAALC expression were confirmed as independent risk factors predicting inferior DFS (CEBPA, hazard ratio 0.066, P = 0.001; BAALC, hazard ratio 3.98, P = 0.003) and inferior OS (CEBPA, hazard ratio 0.125, P = 0.002; BAALC, hazard ratio 4.215, P = 0.001). Data obtained in this study suggest that CEBPA mutation status and BAALC expression are important prognostic factors in AML patients with normal cytogenetics and their incorporation into novel risk-adapted therapeutic strategies may improve the currently disappointing cure rate of this group of patients.
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PMID:Prognostic significance of CEBPA mutations and BAALC expression in acute myeloid leukemia Egyptian patients with normal karyotype. 2030 78

Over expression of BAALC (brain and acute leukemia, cytoplasmic) predicts an inferior outcome in acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. To identify BAALC-associated genes that give insights into its functional role in chemotherapy resistance, gene expression signatures differentiating high from low BAALC expressers were generated from normal CD34(+) progenitors, T-acute lymphoblastic leukemia (T-ALL) and AML samples. The insulin-like growth factor binding protein 7 (IGFBP7) was one of the four genes (CD34, CD133, natriuretic peptide receptor C (NPR3), IGFBP7) coexpressed with BAALC and common to the three entities. In T-ALL, high IGFBP7-expression was associated with an immature phenotype of early T-ALL (P<0.001), expression of CD34 (P<0.001) and CD33 (P<0.001). Moreover, high IGFBP7-expression predicted primary therapy resistance (P=0.03) and inferior survival in T-ALL (P=0.03). In vitro studies revealed that IGFBP7 protein significantly inhibited the proliferation of leukemia cell lines (Jurkat cells: 42% reduction, P=0.002; KG1a cells: 65% reduction, P<0.001). In conclusion, IGFBP7 was identified as a BAALC coexpressed gene. Furthermore, high IGFBP7 was associated with stem cell features and treatment failure in T-ALL. In contrast to BAALC, which likely represents only a surrogate marker of treatment failure in acute leukemia, IGFBP7 regulates the proliferation of leukemic cells and might be involved in chemotherapy resistance.
Leukemia 2010 Aug
PMID:BAALC-associated gene expression profiles define IGFBP7 as a novel molecular marker in acute leukemia. 2053 51

The important role of insulin-like growth factor binding protein 7 (IGFBP7) as a tumor suppressor in solid tumors has been revealed in several studies. Interestingly, in a recent study IGFBP7 was also shown to be aberrantly expressed in acute leukemia. Moreover, in acute T-lymphoblastic leukemia (T-ALL), high IGFBP7 expression predicts primary therapy resistance. In order to elucidate the mechanisms underlying aberrant IGFBP7 expression, we used pyrosequencing technology to investigate the DNA methylation of IGFBP7 in 109 T-ALL patient samples. Aberrant methylation was shown and hypomethylation was associated with an early immunophenotype and co-expression of the stem cell markers CD117 (P < 0.001) and CD34 (P < 0.001). In concordance, gene expression profiles of 86 T-ALL patients revealed upregulation of stem cell markers (CD34 and CD133) as well as genes associated with poor outcome and pathogenesis of leukemia (MN1, BAALC, FLT3) in the high IGFBP7 expression group. In conclusion, aberrant IGFBP7 expression is regulated by DNA methylation in acute leukemia. Hypomethylation of the gene is likely to characterize an immature and a more malignant subtype of the disease.
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PMID:Expression of IGFBP7 in acute leukemia is regulated by DNA methylation. 2104 Feb 19

Cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous disease with variable clinical outcomes. Emerging data has identified molecular markers that provide additional prognostic information to better classify these patients into those with a more favorable prognosis and those with an unfavorable prognosis who may require more aggressive or investigational therapies. Markers such as mutations in nucleophosmin 1 gene and CCAAT/enhancer binding protein alpha gene have been associated with a more favorable prognosis in CN-AML. In contrast, FMS-related tyrosine kinase 3 mutations, partial tandem duplication of mixed-lineage leukemia gene and overexpression of brain and acute leukemia, cytoplasmic gene are associated with inferior clinical outcomes. In this article, the authors discuss the classical clinical features of AML and the importance of cytogenetics that predict prognosis in AML. They review the best-described molecular markers in CN-AML and their significance to clinical decision making in CN-AML.
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PMID:Prognostically important molecular markers in cytogenetically normal acute myeloid leukemia. 2152 52

To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.
Leukemia 2012 Feb
PMID:Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia. 2182 63

BAALC expression is an indicator of aggressiveness in acute myelogenous leukemia (AML). Overexpression of this gene is associated to poor of clinical outcome. It is known that post-translational histone modifications control gene transcription. Thus, here we have investigated BAALC expression and post-translational histone modifications in leukemia cell lines. We show that Kasumi-6 and Kyo cells have high and low BAALC mRNA levels, respectively. Moreover, we demonstrate that these cell lines present distinct profiles in terms of histone post-translational modifications (H3K9K14 acetylation, H3K4 trimethylation and H3K23 trimethylation) at the level of BAALC promoter. These findings, in light of recent data on how histone post-translational modifications control gene expression, indicate that BAALC gene is "paused" and that in leukemia cells its transcription can be activated or repressed by mechanisms acting on epigenetic marks.
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PMID:Histone post-translational modifications associated to BAALC expression in leukemic cells. 2219 54


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